Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors

ABSTRACT

The present disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: 
                         
where R 1 , R 2 , R 3 , R 4 , R 4′ , X 1 , Y 1 , Y 2 , Y 3 , Y 4 , n, and m are described herein.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/837,393, filed Dec. 11, 2017, which is a continuation of U.S.application Ser. No. 15/015,571, filed Feb. 4, 2016, no U.S. Pat. No.9,840,491, which claims the benefit of and priority to U.S. provisionalapplication No. 62/112,487, filed Feb. 5, 2015, the entire contents ofeach of which are incorporated herein by reference in its entirety.

FIELD OF DISCLOSURE

The present disclosure is directed to inhibitors of ubiquitin-specificprotease 7 (USP7) useful in the treatment of diseases or disordersassociated with USP7 enzymes. Specifically, the disclosure is concernedwith compounds and compositions inhibiting USP7, methods of treatingdiseases or disorders associated with USP7, and methods of synthesis ofthese compounds.

BACKGROUND OF THE DISCLOSURE

Ubiquitination is a post translational modification initially identifiedas a crucial component of proteasomal degradation in the ubiquitinproteasome system (UPS). Chains of Ubiquitin (Ub(s)), an 8.5 kDa highlyconserved protein, are covalently attached to substrates to be degradedin the proteasome. (Finley D. “Recognition and processing ofubiquitin-protein conjugates by the proteasome.” Annual review ofbiochemistry 78:477-513, (2009)) The molecular mechanisms by which theUPS acts are also varied, with different chain linkages ofubiquitination controlling protein turnover, enzymatic activity,subcellular localization, and protein-protein interactions of substrateproteins. (Komander D., et. al. “The emerging complexity of proteinubiquitination,” Biochem. Soc. Trans. 37(Pt 5):937-53 (2009))

Ubiquitin-specific protease 7 (USP7) is a Ubiquitin Specific Protease(USP) family deubiquitinase (DUB) that was originally identified as anenzyme that interacted with virally-encoded proteins of the Herpessimplex virus and later the Epstein-Barr virus. (Everett R. D., MeredithM., Orr A., Cross A, Kathoria M., Parkinson J. “A novelubiquitin-specific protease is dynamically associated with the PMLnuclear domain and binds to a herpes virus regulatory protein,” EMBO J.16(7):1519-30 (1997); Holowaty M. N., Zeghouf M., Wu H., et al. “Proteinprofiling with Epstein-Barr nuclear antigen-1 reveals an interactionwith the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7,”J. Biol. Chem. 278(32):29987-94 (2003)) Ubiquitin Specific Proteases(USPs) specifically cleave the isopeptide bond at the carboxy terminusof ubiquitin. In contrast to other DUB classes, which are thought togenerally regulate ubiquitin homeostasis or to be involved inpre-processing of linear ubiquitin chains, USPs remove ubiquitin fromspecific targets. Given this substrate specificity combined with thenumerous roles ubiquitination has in the cell, USPs are importantregulators of a multitude of pathways, ranging from preventing theproteolysis of ubquitinated substrates, to controlling their nuclearlocalization.

USP7 deubiquitinates a variety of cellular targets involved in differentprocesses related to cancer and metastasis, neurodegenerative diseases,immunological disorders, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, and bacterial infections and diseases.

For example, USP7 has been shown to stabilize DNMT1, a DNAmethyltransferase that maintain epigenetic silencing, to maintain highersteady state-levels of Claspin, a protein involved in ataxiatelangiectasia and Rad3-related (ATR) phosphorylation of Chk1, and toregulate Tip60 protein levels, a histone acetyltransferase andtranscriptional coregulator involved in adipogenesis. (Zhanwen du, SongJ., Wang Y., et al. “DNMT1 stability is regulated by proteinscoordinating deubiquitination and acetylation-driven ubiquitination,”Science Signaling 3(146) (2010); Faustrup H., Bekker-Jensen S., BartekJ., Lukas J., Mail N., Mailand N. “USP7 counteracts SCFbetaTrCP- but notAPCCdh1-mediated proteolysis of Claspin,” The Journal of cell biology184(1):13-9 (2009); Gao Y., Koppen A., Rakhsh M., et al. “Earlyadipogenesis is regulated through USP7-mediated deubiquitination of thehistone acetyltransferase TIP60,” Nature Communications 4:2656 (2013)

In addition to regulating the protein stability of poly-ubiquitinatedtargets, USP7 also acts to control the subcellular localization ofproteins. Mono-ubiquitination of PTEN has been shown to effect itscytoplasmic/nuclear partitioning, where nuclear localization of PTEN isimportant for its tumor suppression activity. (Trotman L. C., Wang X.,Alimonti A., et al. “Ubiquitination regulates PTEN nuclear import andtumor suppression,” Cell 128(1):141-56 (2007); Song M. S., Salmena L.,Carracedo A., et al. “The deubiquitinylation and localization of PTENare regulated by a HAUSP-PML network,” Nature 455(7214):813-7 (2008))USP7 has also been shown to bind and deubiquitinate FOXO4, a member ofthe FOXO subfamily of transcription factors involved in a variety ofcell processes including metabolism, cell cycle regulation apoptosis,and response to oxidative stress, decreasing its nuclear localizationand transcriptional activity. (van der Horst A., van der Horst O., deVries-Smits A. M. M., et al. “FOXO4 transcriptional activity isregulated by monoubiquitination and USP7/HAUSP,” Nat. Cell Biol.8(10):1064-73 (2006))

Cellular targets of USP7 also include the tumor suppressor p53 and itsmajor E3 ligase, MDM2, stabilizing p53 via the degradation of MDM2. (LiM., Chen D., Shiloh A., et al. “Deubiquitination of p53 by HAUSP is animportant pathway for p53 stabilization,” Nature 416(6881):648-53(2002); Li M., Brooks C. L., Kon N., Gu W. “A dynamic role of HAUSP inthe p53-Mdm2 pathway,” Mol. Cell. 13(6):879-86 (2004)) Structuralstudies have also shown that the EBNA1 protein encoded by theEpstein-Barr virus interacts at the same binding surface as USP7 on p53,preventing USP7 endogenous cellular activity while recruiting USP7 toviral promoters in order to activate latent viral gene expression.(Saridakis V., et al. “Structure of the p53 binding domain of HAUSP/USP7bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediatedimmortalization,” Mol. Cell. 18(1):25-36 (2005); Sarkari F.,Sanchez-Alcaraz T., Wang S., Holowaty M. N., Sheng Y., Frappier L.“EBNA1-mediated recruitment of a histone H2B deubiquitylating complex tothe Epstein-Barr virus latent origin of DNA replication,” PLoS pathogens5(10) (2009); Sheng Y., et al. “Molecular recognition of p53 and MDM2 byUSP7/HAUSP,” Nat. Struct. Mol. Biol. 13(3):285-91 (2006)) Similarly, thegene product of TSPYL5, a gene frequently amplified in breast cancer andassociated with poor clinical outcome, alters the ubiquitination statusof p53 via its interaction with USP7. (Epping M. T., et al. “TSPYL5suppresses p53 levels and function by physical interaction with USP7,”Nat. Cell Biol. 13(1):102-8 (2011))

Inhibition of USP7 with small molecule inhibitors therefore has thepotential to be a treatment for cancers and other disorders. For thisreason, there remains a considerable need for novel and potent smallmolecule inhibitors of USP7.

SUMMARY OF THE DISCLOSURE

A first aspect of the disclosure relates to compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

Y₁ is N or CH;

Y₂ is N or CR₅;

Y₃ is N or CR₆;

Y₄ iS N or CR₇;

R₁ is H, —OH, —SH, —NH₂, or F;

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₄ and R_(4′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, or CN;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)haloalkyl, halogen, NO₂, or CN, wherein the alkyl, alkenyl, and alkynylare optionally substituted with one or more R₁₂;

R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃;

R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl, —N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

wherein R₅, R₆, and R₇ are not all simultaneously H;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₂ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₅;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₆;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

q is independently at each occurrence 0, 1, or 2; and

provided that when R₂ is optionally substituted alkyl, R₅ is H, and R₇is H, R₆ is not chloro.

Another aspect of the present disclosure relates to a method of treatinga disease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present disclosure is directed to a method ofinhibiting USP7. The method involves administering to a patient in needthereof an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to a method of treatingcancer. The method comprises administering to a patient in need thereofan effective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the present disclosure relates to a method of treatinga neurodegenerative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to a method of treatinga viral infection or disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to a method of treatingan inflammatory disease or condition. The method comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to a method of inducingcell cycle arrest, apoptosis in tumor cells and/or enhancedtumor-specific T-cell immunity. The method comprises contacting thecells with an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the present disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof and a pharmaceutically acceptable carrier. The pharmaceuticalacceptable carrier may further include an excipient, diluent, orsurfactant.

Another aspect of the present disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in the manufactureof a medicament for treating a disease associated with inhibiting USP7.

Another aspect of the present disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment ofa disease associated with inhibiting USP7.

The present disclosure further provides methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

The present disclosure provides inhibitors of USP7 that are therapeuticagents in the treatment of diseases such as cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present disclosure further provides compounds and compositions withan improved efficacy and safety profile relative to known USP7inhibitors. The present disclosure also provides agents with novelmechanisms of action toward USP7 enzymes in the treatment of varioustypes of diseases including cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases. Ultimately thepresent disclosure provides the medical community with a novelpharmacological strategy for the treatment of diseases and disordersassociated with USP7 enzymes.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure relates to compounds and compositions that arecapable of inhibiting the activity USP7. The disclosure features methodsof treating, preventing or ameliorating a disease or disorder in whichUSP7 plays a role by administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. The methods of the present disclosurecan be used in the treatment of a variety of USP7 dependent diseases anddisorders by inhibiting the activity of USP7 enzymes. Inhibition of USP7provides a novel approach to the treatment, prevention, or ameliorationof diseases including, but not limited to, cancer and metastasis,neurodegenerative diseases, immunological disorders, osteoporosis,arthritis inflammatory disorders, cardiovascular diseases, ischemicdiseases, viral infections and diseases, and bacterial infections anddiseases.

In a first aspect of the disclosure, the compounds of Formula (I) aredescribed:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein R₁, R₂, R₃, R₄, R_(4′),X₁, Y₁, Y₂, Y₃, Y₄, m, and n are as described herein above.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (e.g., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have sub stituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, —OH, —CN, —COOH, —CN₂CN,—O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl,—C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl),—N((C₁-C₆) alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl,—S(O)₂(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂.The substituents can themselves be optionally substituted. “Optionallysubstituted” as used herein also refers to substituted or unsubstitutedwhose meaning is described below.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, —O—(C₂-C₆) alkenyl,—O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂,—OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, NH₂,NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂, —S(O)₂—(C₁-C₆) alkyl,—S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include, but are not limited to,phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, andthe like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain,e.g., —O(alkyl). Examples of alkoxy groups include, without limitation,methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl,pentenyl, or hexenyl. An alkenyl group can be unsubstituted orsubstituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynylgroup can be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical.Any of the above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. As herein defined,alkylene may also be a C₁-C₆ alkylene. An alkylene may further be aC₁-C₄ alkylene. Typical alkylene groups include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Cycloalkyl” or “carbocyclyl” means monocyclic or polycyclic saturatedcarbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof.A C₃-C₈ cycloalkyl is a cycloalkyl group containing between 3 and 8carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged(e.g., norbornane).

“Heterocyclyl” or “heterocycloalkyl” monocyclic or polycyclic ringscontaining carbon and heteroatoms taken from oxygen, nitrogen, or sulfurand wherein there is not delocalized π electrons (aromaticity) sharedamong the ring carbon or heteroatoms. The heterocycloalkyl ringstructure may be substituted by one or more substituents. Thesubstituents can themselves be optionally substituted. Examples ofheterocyclyl rings include, but are not limited to, oxetanyl,azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl,thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl,and homotropanyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more —OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, e.g., C≡N.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom (e.g., NH₂).

The term “alkylamino” as used herein refers to an amino or NH₂ groupwhere one of the hydrogens has been replaced with an alkyl group, asdefined herein above, e.g., —NH(alkyl). Examples of alkylamino groupsinclude, but are not limited to, methylamino (e.g., —NH(CH₃)),ethylamino, propylamino, iso-propylamino, n-butylamino, sec-butylamino,tert-butylamino, etc.

The term “dialkylamino” as used herein refers to an amino or NH₂ groupwhere both of the hydrogens have been replaced with alkyl groups, asdefined herein above, e.g., —N(alkyl)₂. The alkyl groups on the aminogroup can be the same or different alkyl groups. Example of dialkylaminogroups include, but are not limited to, dimethylamino (e.g., —N(CH₃)₂),diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino,di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,methyl(butylamino), etc.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ringsystems with both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A (C₃-C₁₂)spirocycloalkyl is a spirocycle containing between 3 and 12 carbonatoms. One or more of the carbon atoms can be substituted with aheteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood tomean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the disclosuremay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumerate, fiunarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

The present disclosure relates to compounds or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, capable of inhibiting USP7, which are useful for thetreatment of diseases and disorders associated with modulation of a USP7enzyme. The disclosure further relates to compounds, or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, which are useful for inhibiting USP7.

In one embodiment, the compounds of Formula (I) have the structure ofFormula (Ia):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)haloalkyl, halogen, NO₂, or CN, wherein the alkyl, alkenyl, and alkynylare optionally substituted with one or more R₁₂;

R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃;

R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl-N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

wherein R₅, R₆, and R₇ are not all simultaneously H;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₂ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₅;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₆;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

q is independently at each occurrence 0, 1, or 2; and

provided that when R₂ is optionally substituted alkyl, R₅ is H, and R₇is H, R₆ is not chloro.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ib):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)haloalkyl, halogen, NO₂, or CN, wherein the alkyl, alkenyl, and alkynylare optionally substituted with one or more R₁₂;

R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃;

R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl, —N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

wherein R₅, R₆, and R₇ are not all simultaneously H;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₂ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₅;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₆;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

q is independently at each occurrence 0, 1, or 2; and

provided that when R₂ is optionally substituted alkyl, R₅ is H, and R₇is H, R₆ is not chloro.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ic):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃;

R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl, —N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

wherein R₆ and R₇ are not both simultaneously H;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₅;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₆;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

q is independently at each occurrence 0, 1, or 2; and

provided that when R₂ is optionally substituted alkyl and R₇ is H, R₆ isnot chloro.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Id):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₆ is D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₅;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

q is independently at each occurrence 0, 1, or 2; and

provided that when R₂ is optionally substituted alkyl, R₆ is not chloro.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ie):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₇ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl, —N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₆;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (If):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)haloalkyl, halogen, NO₂, or CN, wherein the alkyl, alkenyl, and alkynylare optionally substituted with one or more R₁₂;

R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃;

R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl, —N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₂ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₅;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₆;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3;

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ig):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)haloalkyl, halogen, NO₂, or CN, wherein the alkyl, alkenyl, and alkynylare optionally substituted with one or more R₁₂;

R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃;

R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl, —N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₂ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)OR₂₇, —NR₂₆C(O)R₂₇, halogen,—P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₅;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)OR₂₇, —NR₂₆C(O)R₂₇, halogen,—P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₆;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ih):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)haloalkyl, halogen, NO₂, or CN, wherein the alkyl, alkenyl, and alkynylare optionally substituted with one or more R₁₂;

R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl,NH-aryl, —N((C₁-C₆) alkyl)-heteroaryl, or —NH-heteroaryl, wherein thealkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₄;

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₂ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino;

each R₁₄ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₆;

each R₁₆ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl, —OH,or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₈;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

each R₂₈ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ii):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, —NR₁₀R₁₁, or —OR₁₀, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀; or

two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₂₀; or two R₃ together whenattached to the same carbon atom form a spiroheterocycloalkyl optionallysubstituted with one or more R₂₀; or two R₃ together when on adjacentcarbons form an aryl ring optionally substituted with one or more R₂₀;or two R₃ together when on adjacent carbons form an heteroaryl ringoptionally substituted with one or more R₂₀;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)haloalkyl, halogen, NO₂, or CN, wherein the alkyl, alkenyl, and alkynylare optionally substituted with one or more R₁₂;

R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₁₃; or

each R₈ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₉; or

two R₈ together when on adjacent atoms form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₉; or two R₈ together when onadjacent atoms form a heterocycloalkyl ring optionally substituted withone or more R₉; or two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉; or two R₈ together whenon adjacent atoms form an heteroaryl ring optionally substituted withone or more R₉;

each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl,heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₉;

R₁₀ and R₁₁ are independently H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl,heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein the alkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionallysubstituted with one or more R₁₇; or

R₁₀ and R₁₁ together with the nitrogen to which they are attached form aheterocycloalkyl ring optionally substituted with one or more R₁₇;

each R₁₂ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino;

each R₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C₃-C₈)cycloalkyl,—C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇, —S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇,—NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇, —NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇,halogen, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, or —SF₅, whereinin the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more R₁₅;

each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₇ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆) hydroxyalkyl, —OH, CN,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one or more R₁₈;

each R₁₈ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl,—S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,—OH, or CN;

each R₁₉ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN;

each R₂₀ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN;

each R₂₁ and R₂₂ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₃ and R₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₂₅;

each R₂₅ is independently at each occurrence (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN;

each R₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

q is independently at each occurrence 0, 1, or 2.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is S. In yet another embodiment, X₁ is S(O).

In some embodiments of the Formulae above, Y₁ is N. In anotherembodiment, Y₁ is CH.

In some embodiments of the Formulae above, Y₂ is N. In anotherembodiment, Y₂ is CR₅.

In some embodiments of the Formulae above, Y₃ is N. In anotherembodiment, Y₃ is CR₆.

In some embodiments of the Formulae above, Y₄ is N. In anotherembodiment, Y₄ is CR₇.

In some embodiments of the Formulae above, R₁ is H, —OH, —SH, —NH₂, orF. In another embodiment, R₁ is H, —OH, or F. In yet another embodiment,R₁ is —OH, or F. In another embodiment, R₁ is —OH.

In some embodiments of the Formulae above, R₂ is (C₁-C₆) alkyl, (C₆-C₁₄)aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl, NR₁₀R₁₁, or—OR₁₀, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one or more R₈. Inanother embodiment, R₂ is (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more R₈. In yet another embodiment, R₂ is(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,heterocycloalkyl, or NR₁₀R₁₁, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one tothree R₈.

In another embodiment, R₂ is (C₁-C₄) alkyl, (C₆-C₁₄) aryl, heteroaryl,or NR₁₀R₁₁, wherein the alkyl, aryl, or heteroaryl are optionallysubstituted with one to three R₈. In yet another embodiment, R₂ is(C₁-C₄) alkyl, (C₆-C₁₄) aryl, or NR₁₀R₁₁, wherein the alkyl and aryl areoptionally substituted with one to three R₈.

In some embodiments of the Formulae above, R₃ is selected from D,(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₂₀. Inanother embodiment, R₃ is selected from D or (C₁-C₆) alkyl, optionallysubstituted with one or more R₂₀. In yet another embodiment, R₃ isselected from D or (C₁-C₆) alkyl, optionally substituted with one tothree R₂₀. In another embodiment, R₃ is selected from D or (C₁-C₄)alkyl, optionally substituted with one to three R₂₀.

In another embodiment, two R₃ together when on adjacent carbons form a(C₃-C₈) cycloalkyl optionally substituted with one or more R₂₀. Inanother embodiment, two R₃ together when attached to the same carbonatom form a (C₃-C₈) spirocycloalkyl optionally substituted with one ormore R₂₀. In another embodiment, two R₃ together when attached to thesame carbon atom form a spiroheterocycloalkyl optionally substitutedwith one or more R₂₀. In another embodiment, two R₃ together when onadjacent carbons form an aryl ring optionally substituted with one ormore R₂₀. In another embodiment, two R₃ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₂₀.

In some embodiments of the Formulae above, R₄ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, halogen, or CN. In another embodiment, R₄ is H, D,(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, orhalogen. In yet another embodiment, R₄ is H, D, (C₁-C₃) alkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, or halogen. In anotherembodiment, R₄ is H, D, (C₁-C₃) alkyl, or halogen. In yet anotherembodiment, R₄ is H, D, methyl, ethyl, propyl, iso-propyl, or halogen.

In some embodiments of the Formulae above, R_(4′) is H, D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, or CN. In another embodiment,R_(4′) is H, D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, or halogen. In yet another embodiment, R_(4′) is H,D, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy,or halogen. In another embodiment, R_(4′) is H, D, (C₁-C₃) alkyl, orhalogen. In yet another embodiment, R_(4′) is H, D, methyl, ethyl,propyl, iso-propyl, or halogen.

In some embodiments of the Formulae above, R₅ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, halogen, NO₂, orCN, wherein the alkyl, alkenyl, and alkynyl are optionally substitutedwith one or more R₁₂. In another embodiment, R₅ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, halogen, NO₂, orCN, wherein the alkyl, alkenyl, and alkynyl are optionally substitutedwith one to three R₁₂. In yet another embodiment, R₅ is H, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, halogen, NO₂, or CN, wherein the alkyl isoptionally substituted with one to three R₁₂. In another embodiment, R₅is H or (C₁-C₆) alkyl optionally substituted with one to three R₁₂.

In some embodiments of the Formulae above, R₆ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂, —NHC(O)(C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one or more R₁₃. In another embodiment,R₆ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, NO₂, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one to three R₁₃. Inyet another embodiment, R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, orheterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one to three R₁₃. Inanother embodiment, R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂,—NHC(O)(C₁-C₆) alkyl, (C₆-C₁₄) aryl, or heteroaryl, wherein the alkyl,aryl, and heteroaryl are optionally substituted with one to three R₁₃.

In some embodiments of the Formulae above, R₇ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl, NH-aryl, —N((C₁-C₆)alkyl)-heteroaryl, or —NH-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₁₄. In another embodiment, R₇ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, heterocycloalkyl,—O-aryl, —O-heteroaryl, —N((C₁-C₆) alkyl)-aryl, NH-aryl, —N((C₁-C₆)alkyl)-heteroaryl, or —NH-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₁₄. In yet another embodiment, R₇ is H, (C₁-C₆)alkyl, (C₆-C₁₄) aryl, heteroaryl, —O-aryl, or —O-heteroaryl, wherein thealkyl, aryl, and heteroaryl are optionally substituted with one to threeR₁₄. In another embodiment, R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, or—O-aryl, wherein the alkyl and aryl are optionally substituted with oneto three R₁₄.

In some embodiments of the Formulae above, each R₈ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN,—(C₁-C₃)-alkylene-O—(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocycloalkyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, —C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂,—S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂, —NR₂₁S(O)_(q)R₂₂,—(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂, —NR₂₁C(O)C(O)R₂₂,—NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅, or—OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more R₉. Inanother embodiment, each R₈ is D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —(C₁-C₃)-alkylene-O—(C₁-C₆)alkyl, —(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₈)cycloalkyl, —S-heteroaryl,—C(O)R₂₁, —CO(O)R₂₁, —C(O)NR₂₁R₂₂, —S(O)_(q)R₂₁, —S(O)_(q)NR₂₁R₂₂,—NR₂₁S(O)_(q)R₂₂, —(C₀-C₃)-alkylene-NR₂₁R₂₂, —NR₂₁C(O)R₂₂,—NR₂₁C(O)C(O)R₂₂, —NR₂₁C(O)NR₂₁R₂₂, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂,—SiMe₃, —SF₅, or —OR₂₁, wherein the alkyl, alkylene, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one tothree R₉.

In another embodiment, two R₈ together when on adjacent atoms form a(C₃-C₈) cycloalkyl optionally substituted with one or more R₉. In yetanother embodiment, two R₈ together when on adjacent atoms form aheterocycloalkyl ring optionally substituted with one or more R₉. Inanother embodiment, two R₈ together when on adjacent atoms form an arylring optionally substituted with one or more R₉. In yet anotherembodiment, two R₈ together when on adjacent atoms form an heteroarylring optionally substituted with one or more R₉.

In some embodiments of the Formulae above, R₉ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈)cycloalkyl, heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₁₉. In another embodiment, R₉ is independently (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,(C₃-C₈) cycloalkyl, heterocycloalkyl, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl,—(C₀-C₃)-alkylene-heteroaryl, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄,—NR₂₃C(O)R₂₄, —NR₂₃R₂₄, —S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄,—NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃,—SF₅, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₁₉.

In some embodiments of the Formulae above, R₁₀ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one or more R₁₇. In another embodiment,R₁₀ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one to three R₁₇.

In some embodiments of the Formulae above, R₁₁ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkylare optionally substituted with one or more R₁₇. In another embodiment,R₁₁ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are optionally substituted with one to three R₁₇.

In another embodiment, R₁₀ and R₁₁ together with the nitrogen to whichthey are attached form a heterocycloalkyl ring optionally substitutedwith one or more R₁₇. In yet another embodiment, R₁₀ and R₁₁ togetherwith the nitrogen to which they are attached form a heterocycloalkylring optionally substituted with one to three R₁₇.

In some embodiments of the Formulae above, R₁₂ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆)alkylamino. In another embodiment, R₁₂ is (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, CN, —C(O)(C₁-C₄) alkyl,—S(O)_(q)(C₁-C₄) alkyl, —NH₂, (C₁-C₄) alkylamino, or di(C₁-C₄)alkylamino.

In some embodiments of the Formulae above, R₁₃ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH,—NH₂, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇,—S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇, —NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇,—NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇, halogen, —P(O)((C₁-C₆) alkyl)₂,—P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₅. In another embodiment, R₁₃ is D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇,—S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇, —NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇,—NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇, halogen, —P(O)((C₁-C₆) alkyl)₂,—P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one tothree R₁₅.

In some embodiments of the Formulae above, R₁₄ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH,—NH₂, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇,—S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇, —NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇,—NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇, halogen, —P(O)((C₁-C₆) alkyl)₂,—P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore R₁₆. In another embodiment, R₁₄ is D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇,—S(O)_(q)NR₂₆R₂₇, —NR₂₆R₂₇, —NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇,—NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇, halogen, —P(O)((C₁-C₆) alkyl)₂,—P(O)(aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one tothree R₁₆.

In some embodiments of the Formulae above, R₁₅ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN. In another embodiment, R₁₅ is (C₁-C₄) alkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen,—C(O)(C₁-C₄) alkyl, —S(O)_(q)(C₁-C₄) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₄) alkylamino, —OH, or CN.

In some embodiments of the Formulae above, R₁₆ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₂₈. In another embodiment, R₁₆ is (C₁-C₄) alkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen,—C(O)(C₁-C₄) alkyl, —S(O)_(q)(C₁-C₄) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₄) alkylamino, (C₆-C₁₄) aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—O—(C₃-C₈)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₂₈.

In some embodiments of the Formulae above, R₁₇ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆)hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂,(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one or more R₁₈. In another embodiment, R₁₇ is (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₁-C₆)hydroxyalkyl, —OH, CN, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂,(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₁₈. In yet another embodiment, R₁₇ is (C₁-C₄) alkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, (C₁-C₄)hydroxyalkyl, —OH, CN, —C(O)(C₁-C₄) alkyl, —S(O)_(q)(C₁-C₄) alkyl, —NH₂,(C₁-C₄) alkylamino, di(C₁-C₄) alkylamino, (C₆-C₁₄) aryl, heteroaryl,(C₅-C₈) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₁₈.

In some embodiments of the Formulae above, R₁₈ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN. In another embodiment, R₁₈ is (C₁-C₄) alkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen,—C(O)(C₁-C₄) alkyl, —S(O)_(q)(C₁-C₄) alkyl, —NH₂, (C₁-C₄) alkylamino,di(C₁-C₄) alkylamino, —OH, or CN.

In some embodiments of the Formulae above, R₁₉ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN. In another embodiment, R₁₉ is (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, —NR₂₆C(O)R₂₇,—NR₂₆S(O)_(q)R₂₇, —C(O)R₂₆, —C(O)NR₂₆R₂₇, —NR₂₆R₂₇, —S(O)_(q)R₂₆,—S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂, —P(O)(aryl)₂, —SiMe₃, —SF₅,—OH, or CN.

In some embodiments of the Formulae above, R₂₀ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, orCN. In another embodiment, R₂₀ is (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, halogen, —OH, —NH₂, or CN.

In some embodiments of the Formulae above, R₂₁ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₅. In another embodiment, R₂₁ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₅.

In some embodiments of the Formulae above, R₂₂ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₅. In another embodiment, R₂₂ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₅.

In some embodiments of the Formulae above, R₂₃ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₅. In another embodiment, R₂₃ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₅.

In some embodiments of the Formulae above, R₂₄ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl are optionally substituted with one ormore R₂₅. In another embodiment, R₂₄ is H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl,or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₅.

In some embodiments of the Formulae above, R₂₅ is (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, or CN. Inanother embodiment, R₂₅ is (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, halogen, —OH, or CN.

In some embodiments of the Formulae above, R₂₆ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino. In anotherembodiment, R₂₆ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to threesubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, —NH₂, (C₁-C₆) alkylamino, ordi(C₁-C₆) alkylamino.

In some embodiments of the Formulae above, R₂₇ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, heteroaryl, (C₅-C₈)cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino. In anotherembodiment, R₂₇ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl,(C₆-C₁₄) aryl, heteroaryl, (C₅-C₈) cycloalkyl, or heterocycloalkyl,wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to threesubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, —NH₂, (C₁-C₆) alkylamino, ordi(C₁-C₆) alkylamino.

In some of the embodiments of the Formulae above, R₂₈ is (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,—C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, —OH, or CN. In another embodiment, R₂₈ is (C₁-C₄)alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen,—C(O)(C₁-C₄) alkyl, —S(O)_(q)(C₁-C₄) alkyl, —NH₂, (C₁-C₄) alkylamino,di(C₁-C₄) alkylamino, —OH, or CN.

In some embodiments of the Formulae above, m is 0, 1, 2, 3, or 4. Inanother embodiment, m is 0, 1, 2, or 3. In yet another embodiment, m is0, 1, or 2. In another embodiment, m is 0 or 1. In yet anotherembodiment, m is 0. In another embodiment, m is 1. In yet anotherembodiment, m is 2. In yet another embodiment, m is 3. In yet anotherembodiment, m is 4.

In some embodiments of the Formulae above, n is 0, 1, 2, or 3. Inanother embodiment, n is 0, 1, or 2. In yet another embodiment, n is 0or 1. In another embodiment, n is 0. In yet another embodiment, n is 1.In another embodiment, n is 2. In yet another embodiment, n is 3.

In some embodiments of the Formulae above, q is 0, 1, or 2. In anotherembodiment, q is 0. In yet another embodiment, q is 1. In anotherembodiment, q is 2.

In some embodiments of the Formulae above, X₁ is C.

In some embodiments of the Formulae above, R₁ is —OH.

In some embodiments of the Formulae above, R₂ is (C₁-C₆) alkyl or(C₆-C₁₄) aryl, wherein the alkyl and aryl are optionally substitutedwith one or more R₈.

In some embodiments of the Formulae above, R₄ is H.

In some embodiments of the Formulae above, R_(4′) is H.

In some embodiments of the Formulae above, Y₂ is N or CR₅ and R₅ is H.

In some embodiments of the Formulae above, Y₃ is N or CR₆ and R₆ is H,(C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂, —NHC(O)(C₁-C₆) alkyl, or (C₆-C₁₄)aryl, wherein the alkyl, and aryl are optionally substituted with one ormore R₁₃.

In some embodiments of the Formulae above, Y₄ is N or CR₇ and R₇ is H,(C₁-C₆) alkyl, (C₆-C₁₄) aryl, or —O-aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₁₄.

In some embodiments of the Formulae above, n is 1.

In some embodiments of the Formulae above, R₅, R₆, and R₇ are not allsimultaneously H.

In some embodiments of the Formulae above, R₂ is optionally substitutedalkyl, R₅ is H, R₇ is H, and R₆ is not chloro.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and Y₁ is CH. In yet another embodiment, X₁ is C, Y₁is CH, and Y₂ is CR₅. In another embodiment, X₁ is C, Y₁ is CH, Y₂ isCR₅, and Y₃ is CR₆. In another embodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅,Y₃ is CR₆, and Y₄ is CR₇. In yet another embodiment, X₁ is C, Y₁ is CH,Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, and R₁ is OH. In another embodiment, X₁is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, and R₂ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈. In yet another embodiment,X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, and R₄ is H. In anotherembodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ isOH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, R₄ is H, and R_(4′) is H. Inanother embodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇,R₁ is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl andaryl are optionally substituted with one or more R₈, R₄ is H, R^(4′) isH, and R₅ is H. In yet another embodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅,Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl,wherein the alkyl and aryl are optionally substituted with one or moreR₈, R₄ is H, R_(4′) is H, R₅ is H, and R₆ is H, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, —NH₂, —NHC(O)(C₁-C₆) alkyl, or (C₆-C₁₄) aryl, wherein the alkyl,and aryl are optionally substituted with one or more R₁₃. In anotherembodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ isOH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, R₄ is H, R_(4′) is H, R₅ isH, R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂, —NHC(O)(C₁-C₆) alkyl,or (C₆-C₁₄) aryl, wherein the alkyl, and aryl are optionally substitutedwith one or more R₁₃, and R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, or—O-aryl, wherein the alkyl and aryl are optionally substituted with oneor more R₁₄.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and Y₁ is N. In yet another embodiment, X₁ is C, Y₁is N, and Y₂ is CR₅. In another embodiment, X₁ is C, Y₁ is N, Y₂ is CR₅,and Y₃ is CR₆. In another embodiment, X₁ is C, Y₁ is N, Y₂ is CR₅, Y₃ isCR₆, and Y₄ is CR₇. In yet another embodiment, X₁ is C, Y₁ is N, Y₂ isCR₅, Y₃ is CR₆, Y₄ is CR₇, and R₁ is OH. In another embodiment, X₁ is C,Y₁ is N, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, and R₂ is (C₁-C₆)alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl are optionallysubstituted with one or more R₈. In yet another embodiment, X₁ is C, Y₁is N, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or(C₆-C₁₄) aryl, wherein the alkyl and aryl are optionally substitutedwith one or more R₈, and R₄ is H. In another embodiment, X₁ is C, Y₁ isN, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or(C₆-C₁₄) aryl, wherein the alkyl and aryl are optionally substitutedwith one or more R₈, R₄ is H, and R_(4′) is H. In yet anotherembodiment, X₁ is C, Y₁ is N, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH,R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, R₄ is H, R_(4′) is H, and R₅is H. In another embodiment, X₁ is C, Y₁ is N, Y₂ is CR₅, Y₃ is CR₆, Y₄is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein thealkyl and aryl are optionally substituted with one or more R₈, R₄ is H,R_(4′) is H, R₅ is H, and R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂,—NHC(O)(C₁-C₆) alkyl, or (C₆-C₁₄) aryl, wherein the alkyl, and aryl areoptionally substituted with one or more R₁₃. In yet another embodiment,X₁ is C, Y₁ is N, Y₂ is CR₅, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, R₄ is H, R_(4′) is H, R₅ isH, R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂, —NHC(O)(C₁-C₆) alkyl,or (C₆-C₁₄) aryl, wherein the alkyl, and aryl are optionally substitutedwith one or more R₁₃, and R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, or—O-aryl, wherein the alkyl and aryl are optionally substituted with oneor more R₁₄.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and Y₁ is CH. In yet another embodiment, X₁ is C, Y₁is CH, and Y₂ is N. In another embodiment, X₁ is C, Y₁ is CH, Y₂ is N,and Y₃ is CR₆. In yet another embodiment, X₁ is C, Y₁ is CH, Y₂ is N, Y₃is CR₆, and Y₄ is CR₇. In another embodiment, X₁ is C, Y₁ is CH, Y₂ isN, Y₃ is CR₆, Y₄ is CR₇, and R₁ is OH. In yet another embodiment, X₁ isC, Y₁ is CH, Y₂ is N, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, and R₂ is (C₁-C₆)alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl are optionallysubstituted with one or more R₈. In another embodiment, X₁ is C, Y₁ isCH, Y₂ is N, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or(C₆-C₁₄) aryl, wherein the alkyl and aryl are optionally substitutedwith one or more R₈, and R₄ is H. In yet another embodiment, X₁ is C, Y₁is CH, Y₂ is N, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or(C₆-C₁₄) aryl, wherein the alkyl and aryl are optionally substitutedwith one or more R₈, R₄ is H, and R_(4′) is H. In yet anotherembodiment, X₁ is C, Y₁ is CH, Y₂ is N, Y₃ is CR₆, Y₄ is CR₇, R₁ is OH,R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, R₄ is H, R_(4′) is H, and R₆is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂, —NHC(O)(C₁-C₆) alkyl, or(C₆-C₁₄) aryl, wherein the alkyl, and aryl are optionally substitutedwith one or more R₁₃. In another embodiment, X₁ is C, Y₁ is CH, Y₂ is N,Y₃ is CR₆, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl,wherein the alkyl and aryl are optionally substituted with one or moreR₈, R₄ is H, R_(4′) is H, R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂,—NHC(O)(C₁-C₆) alkyl, or (C₆-C₁₄) aryl, wherein the alkyl, and aryl areoptionally substituted with one or more R₁₃, and R₇ is H, (C₁-C₆) alkyl,(C₆-C₁₄) aryl, or —O-aryl, wherein the alkyl and aryl are optionallysubstituted with one or more R₁₄.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and Y₁ is CH. In yet another embodiment, X₁ is C, Y₁is CH, and Y₂ is CR₅. In another embodiment, X₁ is C, Y₁ is CH, Y₂ isCR₅, and Y₃ is N. In yet another embodiment, X₁ is C, Y₁ is CH, Y₂ isCR₅, Y₃ is N, and Y₄ is CR₇. In another embodiment, X₁ is C, Y₁ is CH,Y₂ is CR₅, Y₃ is N, Y₄ is CR₇, and R₁ is OH. In yet another embodiment,X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is N, Y₄ is CR₇, R₁ is OH, and R₂ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈. In another embodiment, X₁ isC, Y₁ is CH, Y₂ is CR₅, Y₃ is N, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆)alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl are optionallysubstituted with one or more R₈, and R₄ is H. In yet another embodiment,X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is N, Y₄ is CR₇, R₁ is OH, R₂ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, R₄ is H, and R_(4′) is H. Inanother embodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is N, Y₄ is CR₇, R₁is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and arylare optionally substituted with one or more R₈, R₄ is H, R_(4′) is H,and R₅ is H. In yet another embodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃is N, Y₄ is CR₇, R₁ is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, whereinthe alkyl and aryl are optionally substituted with one or more R₈, R₄ isH, R_(4′) is H, R₅ is H, and R₇ is H, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, or—O-aryl, wherein the alkyl and aryl are optionally substituted with oneor more R₁₄.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and Y₁ is CH. In yet another embodiment, X₁ is C, Y₁is CH, and Y₂ is CR₅. In another embodiment, X₁ is C, Y₁ is CH, Y₂ isCR₅, and Y₃ is CR₆. In yet another embodiment, X₁ is C, Y₁ is CH, Y₂ isCR₅, Y₃ is CR₆, and Y₄ is N. In another embodiment, X₁ is C, Y₁ is CH,Y₂ is CR₅, Y₃ is CR₆, Y₄ is N, and R₁ is OH. In yet another embodiment,X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is N, R₁ is OH, and R₂ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈. In another embodiment, X₁ isC, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is N, R₁ is OH, R₂ is (C₁-C₆)alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl are optionallysubstituted with one or more R₈, and R₄ is H. In yet another embodiment,X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is N, R₁ is OH, R₂ is(C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and aryl areoptionally substituted with one or more R₈, R₄ is H, and R_(4′) is H. Inanother embodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃ is CR₆, Y₄ is N, R₁is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, wherein the alkyl and arylare optionally substituted with one or more R₈, R₄ is H, R_(4′) is H,and R₅ is H. In yet another embodiment, X₁ is C, Y₁ is CH, Y₂ is CR₅, Y₃is CR₆, Y₄ is N, R₁ is OH, R₂ is (C₁-C₆) alkyl or (C₆-C₁₄) aryl, whereinthe alkyl and aryl are optionally substituted with one or more R₈, R₄ isH, R_(4′) is H, R₅ is H, and R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy,—NH₂, —NHC(O)(C₁-C₆) alkyl, or (C₆-C₁₄) aryl, wherein the alkyl, andaryl are optionally substituted with one or more R₁₃.

Non-limiting illustrative compounds of the disclosure include:

-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-7-methoxyquinazolin-4(3H)-one    (I-1);-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-one    (I-2);-   7-amino-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)quinazolin-4(3H)-one    (I-3);-   N-(3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)acetamide    (I-4);-   (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-7-methoxyquinazolin-4(3H)-one    (I-5);-   (R)-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-one    (I-6);-   3-((1-(1-benzylindoline-5-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-methylquinazolin-4(3H)-one    (I-7);-   3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-phenylquinazolin-4(3H)-one    (I-8);-   3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-8-phenylquinazolin-4(3H)-one    (I-9);-   3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-8-(4-fluorophenoxy)quinazolin-4(3H)-one    (I-10);-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrido[2,3-d]pyrimidin-4(3H)-one    (I-11);-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one    (I-12); and-   3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one    (I-13).

In another embodiment of the disclosure, the compounds of Formula (I)are enantiomers. In some embodiments the compounds are the(S)-enantiomer. In other embodiments the compounds are the(R)-enantiomer. In yet other embodiments, the compounds of Formula (I)may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent disclosure, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the disclosure, and pharmaceutically acceptable salts,hydrates, solvates, stereoisomers and prodrugs thereof may exist intheir tautomeric form (for example, as an amide or imino ether). Allsuch tautomeric forms are contemplated herein as part of the presentdisclosure.

The compounds of the disclosure may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of thedisclosure as well as mixtures thereof, including racemic mixtures, formpart of the present disclosure. In addition, the present disclosureembraces all geometric and positional isomers. For example, if acompound of the disclosure incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the disclosure. Each compound herein disclosed includes allthe enantiomers that conform to the general structure of the compound.The compounds may be in a racemic or enantiomerically pure form, or anyother form in terms of stereochemistry. The assay results may reflectthe data collected for the racemic form, the enantiomerically pure form,or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the disclosure may be atropisomers (e.g.,substituted biaryls) and are considered as part of this disclosure.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the disclosure may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the disclosure. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the disclosure.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this disclosure, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the disclosure. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the disclosure.)Individual stereoisomers of the compounds of the disclosure may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present disclosure can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within thescope of this disclosure. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated.

The present disclosure relates to compounds which are modulators ofUSP7. In one embodiment, the compounds of the present disclosure areinhibitors of USP7.

The disclosure is directed to compounds as described herein andpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, and pharmaceutical compositionscomprising one or more compounds as described herein, orpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present disclosure includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present disclosure can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent disclosure can be synthesized by following the steps outlined inGeneral Schemes 1 and 2 which comprise different sequences of assemblingintermediates Ia-Ih. Starting materials are either commerciallyavailable or made by known procedures in the reported literature or asillustrated.

wherein R₂-R₄, R_(4′), X₁, Y₁, Y₂, Y₃, Y₄, m, and n are defined as inFormula (I).

The general way of preparing compounds of Formula (I) by usingintermediates Ia, Ib, Ic, and Id is outlined in General Scheme 1.Alkylation of Ia with Ib using a base, e.g., cesium carbonate, in asolvent, e.g., dimethylformamide (DMF), at elevated temperature yieldsIc. Deprotection of intermediate Ic using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., 1,2-dichloroethane ordichloromethane (DCM) optionally at elevated temperature yields Id.Acylation of intermediate Id to produce a compound of Formula (I) whereX₁ is C can be accomplished by coupling of an acid under standardcoupling conditions using a coupling reagent, e.g.,2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate Id can be acylated with anacid chloride or carbamoyl chloride using a base, e.g., triethylamine orDIPEA, and in a solvent, e.g., dichloromethane, to produce a compound ofFormula (I) where X₁ is C. For synthesis of compounds of Formula (I)where X₁ is S or S(O), intermediate Id is treated with a sulfonylchloride or a sulfinic chloride and a base, e.g., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane,DMF to provide the desired product of Formula (I).

wherein R₁-R₄, R_(4′), X₁, Y₁, Y₂, Y₃, Y₄, m, and n are defined as inFormula (I).

Alternatively, molecules of Formula I can be prepared usingintermediates Ie, If, Ig, and Ih as outlined in General Scheme 2.Hydrolysis of intermediate Ie with lithium hydroxide in solvent, e.g.,methanol and/or water, provides intermediate If. Coupling of If with Igusing a coupling reagent, e.g.,2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF provides Ih.Cyclization of Ih with trimethyl orthoformate at elevated temperatureprovides the desired product of Formula (I).

A mixture of enantiomers, diastereomers, cis/trans isomers resultingfrom the process described above can be separated into their singlecomponents by chiral salt technique, chromatography using normal phase,reverse phase or chiral column, depending on the nature of theseparation.

It should be understood that in the description and formula shown above,the various groups R₁-R₄, R_(4′), X₁, Y₁, Y₂, Y₃, Y₄, m, n, and othervariables are as defined above, except where otherwise indicated.Furthermore, for synthetic purposes, the compounds of General Schemes 1and 2 are mere representative with elected radicals to illustrate thegeneral synthetic methodology of the compounds of Formula (I) as definedherein.

Methods of Using the Disclosed Compounds

Another aspect of the disclosure relates to a method of treating adisease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount thecompositions and compounds of Formula (I).

In another aspect, the present disclosure is directed to a method ofinhibiting USP7. The method involves administering to a patient in needthereof an effective amount of a compound of Formula (I).

Another aspect of the present disclosure relates to a method oftreating, preventing, inhibiting or eliminating a disease or disorder ina patient associated with the inhibition of USP7, the method comprisingadministering to a patient in need thereof an effective amount of acompound of Formula (I). In one embodiment, the disease or disorder isselected from the group consisting of cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present disclosure also relates to the use of an inhibitor of USP7for the preparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or condition mediated by USP7,wherein the medicament comprises a compound of Formula (I).

In another aspect, the present disclosure relates to a method for themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a disease or condition mediated by USP7, wherein themedicament comprises a compound of Formula (I).

Another aspect of the present disclosure relates to a compound ofFormula (I) for use in the manufacture of a medicament for treating adisease associated with inhibiting USP7.

In another aspect, the present disclosure relates to the use of acompound of Formula (I) in the treatment of a disease associated withinhibiting USP7.

Another aspect of the disclosure relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I).

In another aspect, the present disclosure relates to a method oftreating a neurodegenerative disease. The method comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I).

Another aspect of the disclosure relates to a method of treating a viralinfection and disease. The method comprises administering to a patientin need thereof an effective amount of a compound of Formula (I).

In another aspect, the present disclosure relates to a method oftreating an inflammatory disease or condition. The method comprisesadministering to a patient in need thereof an effective amount of acompound of Formula (I).

Another aspect of the disclosure relates to a method of inducing cellcycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific Tcell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I).

In one embodiment, the present disclosure relates to the use of aninhibitor of USP7 for the preparation of a medicament used in treatment,prevention, inhibition or elimination of a disease or disorderassociated with associated with cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of cancers including, but not limited to, liposarcoma,neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer,multiple myeloma, colorectal cancer, non-small cell lung cancer, HumanPapilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroidor vaginal cancer or Epstein-Barr Virus-associated nasopharyngealcarcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkinlymphoma or diffuse large B-cell lymphoma.

In some embodiments, the patient is selected for treatment based on geneamplification and/or elevated tumor expression of USP7, MDM2 or MDM4relative to tissue-matched expression. In other embodiments, the patientis selected for the treatment based on tumor expression of wild typeTP53 or based on the tumor immune cell composition, specificallyelevated regulatory T lymphocytes, CD4+CD25+FoxP3+ T cells.

In some embodiments, administration of a compound of Formula (I) or apharmaceutical composition comprising a compound of the presentdisclosure and a pharmaceutically acceptable carrier induces a change inthe cell cycle or cell viability.

For example, the change in the cell cycle or cell viability may beindicated by decreased tumor levels of MDM2 protein and/or increasedlevels of TP53, CDKN1A (p21, Cip1), PUMA or BAX or by increasedexpression of one or more p53 target genes. In one embodiment, the p53target genes include, but are not limited to, CDKN1A (p21, Cip1), BBC3(PUMA), BAX or MDM2.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of neurodegenerative diseases including, but not limitedto, Alzheimer's disease, multiple sclerosis, Huntington's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,amyotrophic lateral sclerosis, or encephalitis.

Another embodiment of the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of viral infections and diseases including but not limitedto, herpes simplex-1 or -2 viral infections, hepatitis A, hepatitis C,SARS coronavirus infection and disease, Epstein-Barr virus, rhinoviralinfections and diseases, adenoviral infections and diseases, orpoliomyelitis.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of inflammatory diseases or conditions is associated withmetabolic disorders including, but not limited to, Type II diabetes,insulin resistance cardiovascular disease, arrhythmia, atherosclerosis,coronary artery disease, hypertriglyceridemia, dyslipidemia,retinopathy, nephropathy, neuropathy, or macular edema.

In another embodiment, the present disclosure relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent disclosure and a pharmaceutically acceptable carrier used forthe treatment of inflammatory diseases or conditions is associated withinflammatory bowel diseases including, but not limited to, ileitis,ulcerative colitis, Barrett's syndrome, or Crohn's disease

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I).

One therapeutic use of the compounds or compositions of the presentdisclosure which inhibit USP7 is to provide treatment to patients orsubjects suffering from cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

The disclosed compounds of the disclosure can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564 which ishereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 300 or 400MHz. Spectra are given in ppm (δ) and coupling constants, J, arereported in Hertz. Tetramethylsilane (TMS) was used as an internalstandard. Mass spectra were collected using a Waters ZQ Single Quad MassSpectrometer (ion trap electrospray ionization (ESI)). Purity and lowresolution mass spectral data were measured using Waters Acquity i-classultra-performance liquid chromatography (UPLC) system with Acquity PhotoDiode Array Detector, Acquity Evaporative Light Scattering Detector(ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using WatersMassLynx 4.1 software and purity characterized by UV wavelength 220 nm,evaporative light scattering detection (ELSD) and electrospray positiveion (ESI). (Column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.6mL/min; Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/FormicAcid), Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient:5-100% B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21mins. Preparatory HPLC purifications were conducted on a Waters SunFireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm, Waters XBridge BEH C18OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm with UV detection (Waters 2489UV/998 PDA), Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×150mm, Waters XBridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm, or Waters XSelect CSH C18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm at 254 nm or 220 nm using a standard solvent gradient program(or as designated below).

Abbreviations used in the following examples and elsewhere herein are:

-   -   atm atmosphere    -   br broad    -   BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)    -   DABCO 1,4-diazabicyclo[2.2.2]octane    -   DAST diethylaminosulfur trifluoride    -   DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-c]azepine    -   DIPEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   EI electron ionization    -   ESI electrospray ionization    -   Et ethyl    -   GCMS gas chromatographymass spectrometry    -   h hour(s)    -   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatographymass spectrometry    -   m multiplet    -   Me methyl    -   MHz megahertz    -   min minutes    -   MS molecular sieves    -   MTBE 2-methoxy-2-methylpropane    -   MW microwave    -   NMR nuclear magnetic resonance    -   ppm parts per million    -   RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl    -   s singlet    -   TFA trifluoroacetic acid    -   TLC thin layer chromatography    -   v volume    -   wt weight

Example 1: Intermediate 2-1.3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-7-nitroquinazolin-4(3H)-one

3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-7-nitroquinazolin-4(3H)-one(Intermediate 2-1, 88 mg, 39%) was prepared from7-nitroquinazolin-4(3H)-one (prepared using Method A below, Example 5)and purified by column chromatography eluting with 50 to 100% ethylacetate/hexanes. LCMS (ESI) m/z 451.22 [M+H].

Example 2: Intermediate 2-2. 7-Phenylquinazolin-4(3H)-one

7-Bromoquinazolin-4(3H)-one (1.60 g, 7.12 mmol), phenylboronic acid(1.04 g, 8.56 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (696 mg, 0.852 mmol), sodium carbonate (1.49 g,14.1 mmol), 1,4-dioxane (150 mL) and water (30 mL) were added to a250-mL 3-necked round-bottom flask fitted with a nitrogen inlet,magnetic stir bar and thermometer. The resulting solution was stirredfor 3 h at 100° C., then cooled to room temperature, filtered anddiluted with water (100 mL). The mixture was extracted with ethylacetate (3×100 mL) and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography eluting withdichloromethane/methanol (20:1 v/v) to afford7-phenylquinazolin-4(3H)-one (Intermediate 2-2, 600 mg, 38%). LCMS (ESI)m/z 223 [M+H].

Example 3: Intermediate 2-3. 8-Phenylquinazolin-4(3H)-one

8-Phenylquinazolin-4(3H)-one (Intermediate 2-3, 700 mg, 28%) wasprepared from 8-bromoquinazolin-4(3H)-one according to the procedureused for Intermediate 2-2 (Example 2), and was purified by columnchromatography eluting with dichloromethane/methanol (10:1 v/v). LCMS(ESI) m/z 223 [M+H].

Example 4: Intermediate 2-4.(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl) methanone

Step 1. (4-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone

Trimethylsulfoxonium iodide (2.60 g, 11.8 mmol), sodium hydride (60% inmineral oil, 480 mg, 12.0 mmol) and dimethyl sulfoxide (15 mL) wereadded to a 100-mL round-bottom flask fitted with a nitrogen inlet andmagnetic stir bar. The resulting mixture was stirred for 30 min at roomtemperature. 1-(4-Fluorobenzoyl)piperidin-4-one (2.00 g, 9.04 mmol) wasadded and stirring was continued for an additional 4 h at roomtemperature. The reaction was quenched by the addition of water (30 mL)and extracted with dichloromethane (3×30 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate to afford(4-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (0.75 g,40%). LCMS: (ESI) m/z 236 [M+H].

Step 2.(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl)methanone

Ammonia (7.0 M in methanol, 15 mL, 0.105 mol) and(4-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Step 1, 350mg, 1.49 mmol) were added to a 100-mL round-bottom flask fitted with amagnetic stir bar. The resulting solution was stirred for 3 h at 60° C.,then cooled to room temperature and concentrated under reduced pressure.The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (1:2 v/v) to afford(4-(aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl)methanone(Intermediate 2-4, 0.28 g, 73%). LCMS: (ESI) m/z 253 [M+H]. ¹H NMR (400MHz, DMSO-d⁶) δ 7.47-7.43 (m, 2H), 7.29-7.24 (m, 2H), 4.95 (s, 1H),3.16-2.96 (m, 2H), 2.54-2.52 (m, 2H), 2.25-1.70 (m, 1H), 1.65-1.15 (m,4H) ppm.

Methods for the Synthesis of Compounds of Formula (I)

Method A

Example 5:3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-one(I-2)

Step 1. tert-Butyl4-hydroxy-4-((8-methyl-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate

To a solution of 8-methylquinazolin-4(3H)-one (20 mg, 0.125 mmol) andtert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (33 mg, 0.156 mmol)in DMF (0.625 mL) was added cesium carbonate (122 mg, 0.375 mmol). Thereaction mixture was stirred at 80° C. for 16 h, then cooled to roomtemperature, diluted with ethyl acetate (0.5 mL) and washed with water(0.5 mL). The organic layer was concentrated under reduced pressure toafford tert-butyl4-hydroxy-4-((8-methyl-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate,which was used without further purification. LCMS: (ESI) m/z 396.29[M+Na].

Step 2. 3-((4-Hydroxypiperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-onetrifluoroacetic acid salt

To a solution of tert-butyl4-hydroxy-4-((8-methyl-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate(Step 1) in 1,2-dichloroethane (0.625 mL) was added trifluoroacetic acid(0.096 mL, 1.25 mmol). The reaction mixture was stirred at 50° C. for 2h and then concentrated under reduced pressure to afford3-((4-hydroxypiperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-onetrifluoroacetic acid salt, which was used without further purification.LCMS: (ESI) m/z 274.23 [M+H].

Step 3.3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-one

To 3-((4-hydroxypiperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-onetrifluoroacetic acid salt (Step 2) was added 3-phenylbutanoic acid (0.2M in 1,2-dichloroethane, 0.750 mL, 0.150 mmol), DIPEA (0.109 mL, 0.625mmol) and HATU (57 mg, 0.150 mmol). The reaction mixture was stirred at50° C. for 1 h, then cooled to room temperature, diluted withdichloromethane (0.5 mL) and washed with water (0.5 mL). The organiclayer was concentrated under reduced pressure and the residue waspurified by preparative HPLC to afford3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-8-methylquinazolin-4(3H)-one(I-2, 21.1 mg, 40% over three steps). LCMS (ESI) m/z 420.28 [M+H]. HPLCColumn: XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm.Mobile phase A: Water with 0.1% ammonium hydroxide/Mobile phase B:Acetonitrile with 0.1% ammonium hydroxide. Gradient: 35% B to 100% Bover 6 min. Flow rate: 23 mL/min. Detector: 220 and 254 nm.

Method B

Example 6:7-Amino-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)quinazolin-4(3H)-one(I-4)

Step 1.7-Amino-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)quinazolin-4(3H)-one

Iron (97 mg, 1.74 mmol) and ammonium chloride (4.0 M aqueous, 0.869 mL,3.47 mmol) were added to a solution of3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-7-nitroquinazolin-4(3H)-one(Intermediate 2-1, 78 mg, 0.17 mmol) in ethanol (1.74 mL). The resultingmixture was heated at 80° C. for 1 h, then diluted with saturatedaqueous sodium bicarbonate (2 mL) and extracted with ethyl acetate (4mL). The organic layer was concentrated under reduced pressure. Some ofthe residue was used in subsequent reactions without furtherpurification (92% by weight) and the remainder (8% by weight) waspurified by preparative HPLC to afford7-amino-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)quinazolin-4(3H)-one (I-3, 0.9 mg, 15%). LCMS(ESI) m/z 421.24 [M+H]. HPLC Column: XBridge BEH C18 OBD Prep Column,130 Å, 5 μm, 19 mm×50 mm. Mobile phase A: Water with 0.1% ammoniumhydroxide/Mobile phase B: Acetonitrile with 0.1% ammonium hydroxide.Gradient: 35% B to 100% B over 6 min. Flow rate: 23 mL/min. Detector:220 and 254 nm.

Step 2.N-(3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)acetamide

Acetyl chloride (5 μL, 0.072 mmol) was added to a solution of7-amino-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)quinazolin-4(3H)-one(used crude from Step 1, 17 mg, assumed to be 0.040 mmol) and DIPEA (21μL, 0.120 mmol) in DCE (0.4 mL). The resulting solution was stirred for16 h at 50° C. Additional acetyl chloride (5 μL, 0.072 mmol) was addedand the mixture was stirred for 1 h at 50° C. The reaction mixture wascooled to room temperature, diluted with saturated aqueous sodiumbicarbonate (0.5 mL) and extracted with ethyl acetate (2×0.5 mL). Thecombined organic extracts were concentrated under reduced pressure andthe residue was purified by preparative HPLC to affordN-(3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)acetamide(I-4, 2.1 mg, 11%). LCMS (ESI) m/z 463.24 [M+H]. HPLC Column: XBridgeBEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm. Mobile phase A: Waterwith 0.1% ammonium hydroxide/Mobile phase B: Acetonitrile with 0.1%ammonium hydroxide. Gradient: 35% B to 100% B over 6 min. Flow rate: 23mL/min. Detector: 220 and 254 nm.

Method C

Example 7:3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-8-(4-fluorophenoxy)quinazolin-4(3H)-one (I-10)

Step 1. Methyl 3-(4-fluorophenoxy)-2-nitrobenzoate

Methyl 3-fluoro-2-nitrobenzoate (1.50 g, 7.53 mmol), 4-fluorophenol (840mg, 7.49 mmol), potassium carbonate (5.00 g, 36.2 mmol) and DMF (15 mL)were added to a 100-mL round-bottom flask fitted with a magnetic stirbar. The resulting solution was stirred overnight at 100° C., thencooled to room temperature and diluted with water (40 mL). The resultingsolution was extracted with dichloromethane (3×40 mL) and the organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate to afford methyl3-(4-fluorophenoxy)-2-nitrobenzoate (1.50 g, 68%). LCMS (ESI) m/z 292[M+H].

Step 2. Methyl 2-amino-3-(4-fluorophenoxy)benzoate

Palladium on carbon (10% wt, 0.20 g) was added to a solution of methyl3-(4-fluorophenoxy)-2-nitrobenzoate (Step 1, 1.50 g, 5.15 mmol) in ethylacetate (80 mL) in a 100-mL round-bottom flask fitted with a magneticstir bar. The mixture was stirred for 16 h at room temperature under anatmosphere of hydrogen then filtered and concentrated under reducedpressure to afford methyl 2-amino-3-(4-fluorophenoxy)benzoate which wasused without further purification (1.30 g). LCMS (ESI) m/z 262 [M+H].

Step 3. 2-Amino-3-(4-fluorophenoxy)benzoic acid

Methyl 2-amino-3-(4-fluorophenoxy)benzoate (Step 2, 300 mg, assumed tobe 1.19 mmol), methanol (10 mL), lithium hydroxide (500 mg, 20.9 mmol)and water (3 mL) were added to a 100-mL round-bottom flask fitted with amagnetic stir bar. The resulting solution was stirred for 4 h at roomtemperature, then acidified to pH 2 with hydrochloric acid (1.0 Maqueous). The resulting solution was extracted with dichloromethane(3×20 mL) and the organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford 2-amino-3-(4-fluorophenoxy)benzoic acid (0.2 g) which was used innext step without further purification. LCMS (ESI) m/z 248 [M+H]

Step 4.2-Amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-(4-fluoro-phenoxy)benzamide

2-Amino-3-(4-fluorophenoxy)benzoic acid (Step 3, 0.1 g, assumed to be0.59 mmol),(4-(aminomethyl)-4-hydroxypiperidin-1-yl)(4-fluorophenyl)methanone(Intermediate 2-4, 122 mg, 0.48 mmol), HATU (186 mg, 0.49 mmol), DIPEA(155 mg, 1.20 mmol) and dichloromethane (10 mL) were added to a 100-mLround-bottom flask fitted with a magnetic stir bar. The resultingsolution was stirred for 2 h at room temperature and then concentratedunder reduced pressure. The crude product was purified by preparativeTLC eluting with ethyl acetate to afford2-amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-(4-fluoro-phenoxy)benzamide(0.13 g, 56%). LCMS (ESI) m/z 482 [M+H].

Step 5.3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-8-(4-fluorophenoxy)quinazolin-4(3H)-one

2-Amino-N-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3-(4-fluorophenoxy)benzamide(Step 4, 130 mg, 0.28 mmol) and trimethyl orthoformate (15 mL) wereadded to a 100-mL round-bottom flask fitted with a magnetic stir bar.The resulting solution was stirred overnight at 100° C. The resultingmixture was concentrated under reduced pressure and purified bypreparative HPLC to afford3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-8-(4-fluorophenoxy)quinazolin-4(3H)-one(I-10, 30 mg, 21%). LCMS (ESI) m/z 492.22 [M+H]. ¹H NMR (400 MHz,DMSO-d⁶) δ 8.21 (s, 1H), 7.99-7.96 (m, 1H), 7.53-7.45 (m, 3H), 7.42-7.39(m, 1H), 7.29-7.21 (m, 2H), 7.19-7.16 (m, 2H), 7.02-6.97 (m, 2H), 5.01(s, 1H), 4.18-4.17 (m, 1H), 4.05 (s, 2H), 3.38-3.32 (m, 1H), 3.30-2.90(m, 2H), 1.63-1.62 (m, 2H), 1.53-1.50 (m, 2H) ppm. HPLC Column: WatersHSS C18, 1.8 μm, 2.1 mm×50 mm. XBridge BEH C18 OBD Prep Column, 130 Å, 5μm, 19 mm×50 mm. Mobile phase A: Ammonium bicarbonate (10 mMaqueous)/Mobile phase B: Acetonitrile. Gradient: 5% B to 95% B over 4min. Detector: 220 and 254 nm.

Method D

Example 8:3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-8-(4-fluorophenoxy)quinazolin-4(3H)-one (I-12)

Step 1. tert-Butyl4-hydroxy-4-((4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate

To a solution of pyrido[3,4-d]pyrimidin-4(3H)-one (12 mg, 0.080 mmol)and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21 mg, 0.10mmol) in DMF (0.400 mL) was added cesium carbonate (78 mg, 0.240 mmol).The reaction mixture was stirred at 80° C. for 16 h, then cooled to roomtemperature, diluted with ethyl acetate (0.5 mL) and washed with water(0.5 mL). The organic layer was concentrated under reduced pressure toafford tert-butyl4-hydroxy-4-((4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate,which was used without further purification. LCMS: (ESI) m/z 361.19[M+H].

Step 2.3-((4-Hydroxypiperidin-4-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-onetrifluoroacetic acid salt

To a solution of tert-butyl4-hydroxy-4-((4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate(Step 1) in 1,2-dichloroethane (0.2 mL) was added trifluoroacetic acid(0.062 mL, 0.80 mmol). The reaction mixture was stirred at 50° C. for 2h and then concentrated under reduced pressure to afford3-((4-hydroxypiperidin-4-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-onetrifluoroacetic acid salt, which was used without further purification.LCMS: (ESI) m/z 261.14 [M+H].

Step 3.3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one

To 3-((4-hydroxypiperidin-4-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-onetrifluoroacetic acid salt (Step 2) was added 3-phenylbutanoic acid (0.2M in 1,2-dichloroethane, 0.480 mL, 0.096 mmol), DIPEA (0.070 mL, 0.400mmol) and HATU (37 mg, 0.096 mmol). The reaction mixture was stirred at50° C. for 1 h, then cooled to room temperature, diluted withdichloromethane (0.5 mL) and washed with water (0.5 mL). The organiclayer was concentrated under reduced pressure and the residue waspurified by preparative HPLC to afford3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one(I-12, 17 mg, 52% over three steps). LCMS (ESI) m/z 407.24 [M+H]. HPLCColumn: XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm.Mobile phase A: Water with 0.1% ammonium hydroxide/Mobile phase B:Acetonitrile with 0.1% ammonium hydroxide. Gradient: 35% B to 100% Bover 6 min. Flow rate: 23 mL/min. Detector: 220 and 254 nm.

Biochemical Assays

Example 9: USP7 Assay A (Ubitquin-Rhodamine 110 Assay)

Each assay was performed in a final volume of 15 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 1 mM GSH (L-Glutathione reduced; Sigma #G4251),0.03% BGG (0.22 μM filtered, Sigma, #G7516-25G), and 0.01% Triton X-100(Sigma, #T9284-10L). Nanoliter quantities of either an 8-point or10-point, 3-fold serial dilution in DMSO was pre-dispensed into assayplates (Perkin Elmer, ProxiPlate-384 F Plus, #6008269) for a final testconcentration range of either 25 μM to 11 nM or 25 μM to 1.3 nM,respectively. The final concentration of the enzyme (USP7, constructUSP7 (208-1102) 6*His, Viva Biotech) in the assay was 62.5 pM. Finalsubstrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555)concentration was 25 nM with [Ub-Rh110]<<Km. 5 μL of 2× enzyme was addedto assay plates (pre-stamped with compound) preincubated with USP7 for30 min and then 5 μL of 2×Ub-Rh110 was added to assay plates. Plateswere incubated stacked for 20 min at room temperature before 5 μL ofstop solution (final concentration of 10 mM citric acid in assay buffer(Sigma, #251275-500G)). Fluorescence was read on the Envision(Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on thePheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

Example 10: USP7 Assay B (Ubitquin-Rhodamine 110 Assay)

Each assay was performed in a final volume of 20 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 2 mM CaCl₂ (1M Calcium Chloride solution; Sigma#21114) 1 mM GSH (L-Glutathione reduced; Sigma #G4251), 0.01% Prionex(0.22 μM filtered, Sigma #G-0411), and 0.01% Triton X-100. Stockcompound solutions were stored at −20° C. as 10 mM in DMSO. Up to 1month prior to the assay, 2 mM test compounds were pre-dispensed intoassay plates (Black, low volume; Corning #3820) and frozen at −20° C.Prestamped assay plates were allowed to come to room temperature on theday of the assay. For the screen, 100 nL of 2 mM was pre-dispensed for afinal screening concentration of 10 μM (DMSO_((fc))=0.5%). For follow-upstudies, 250 nL of an 8-point, 3-fold serial dilution in DMSO waspre-dispensed into assay plates for a final test concentration of 25μM-11 nM (1.25% DMSO final concentration). Unless otherwise indicated,all follow-up assays were run on triplecate plates. Enzyme (USP7,construct Met (208-1102)-TEV-6*His; Viva Q93009-1) concentration andincubation times were optimized for the maximal signal-to-backgroundwhile maintaining initial velocity conditions at a fixed substrateconcentration. The final concentration of the enzyme in the assay waseither 75 pM or 250 pM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine110, R&D Systems (biotechne)#U-555) concentration was 25 nM with[Ub-Rh110]<<Km. Pre-stamped with compounds were either not preincubatedor preincubated with USP7 between 30 to 120 min prior to the addition of10 μL of 2×Ub-Rh110 to compound plates. Plates were incubated stackedfor either 23 or 45 min at room temperature before fluorescence was readon the Envision (Excitation at 485 nm and Emission at 535 nm; PerkinElmer) or on the PheraSTAR (Excitation at 485 nm and Emission at 535 nm;BMG Labtech).

Data from USP7 Assays A and B were reported as percent inhibition (inh)compared with control wells based on the following equation: %inh=1−((FLU−Ave_(Low))/(Ave_(High)−Ave_(Low))) where FLU=measuredFluorescence. Ave_(Low)=average Fluorescence of no enzyme control(n=16). Ave_(High)=average Fluorescence of DMSO control (n=16). IC₅₀values were determined by curve fitting of the standard 4 parameterlogistic fitting algorithm included in the Activity Base softwarepackage: IDBS XE Designer Model205. Data is fitted using the LevenburgMarquardt algorithm. IC₅₀ data from USP7 Assays A and B for thecompounds of the disclosure can be found in the Table below.

TABLE 1 USP7 Activity of compounds of the present disclosure in USPAssays A and B. HPLC Method of Intermediate LCMS: (ESI) Retention IC50Example Synthesis In Synthesis m/z [M + H] time/min (μM) I-1 A — 436.271.2 ++++ I-2 A — 420.28 1.3 ++++ I-3 B 2-1 421.24 1.01 ++++ I-4 B 2-1463.24 1.03 ++++ I-5 A — 436.16 1.2 ++++ I-6 A — 420.17 1.31 ++++ I-7 A— 509.19 1.5 ++ I-8 A 2-2 440.15 1.33 + I-9 A 2-3 440.16 1.38 ++ I-10 C2-4 492.22 1.38 ++ I-11 D — 407.28 0.97 + I-12 D — 407.24 0.99 ++ I-13 D— 407.16 0.92 +++ Table 1: USP7 activity of compounds of the disclosurein USP7 assay A and B. ++++ indicates an IC₅₀ of less than about 0.2 μM,+++ indicates an IC₅₀ between about 0.2 μM and about 1 μM, ++ indicatesan IC₅₀ between about 1 μM and about 10 μM, and + indicates an IC₅₀greater than 10 μM.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

We claim:
 1. A compound of Formula (Id):

or a pharmaceutically acceptable salt thereof, wherein: R₂ is (C₁-C₆)alkyl substituted with R₈; each R₃ is independently at each occurrenceselected from D, (C₁-C₆) alkyl, (C₆-C₁₄) aryl, 5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S,(C₃-C₈) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₂₀; or two R₃ together when on adjacent carbons forma (C₃-C₈) cycloalkyl optionally substituted with one to three R₂₀; ortwo R₃ together when attached to the same carbon atom form a (C₃-C₈)spirocycloalkyl optionally substituted with one to three R₂₀; or two R₃together when attached to the same carbon atom form a 3- to 7-memberedspiroheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N,and S, optionally substituted with one to three R₂₀; or two R₃ togetherwhen on adjacent carbons form a (C₆-C₁₄) aryl ring optionallysubstituted with one to three R₂₀; or two R₃ together when on adjacentcarbons form a 5- or 6-membered heteroaryl ring comprising 1 to 3heteroatoms selected from O, N, and S optionally substituted with one tothree R₂₀; R₆ is H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, halogen other than Cl, CN, NO₂, —NH₂, —NHC(O)(C₁-C₆)alkyl, (C₆-C₁₄) aryl, 5- or 6-membered heteroaryl comprising 1 to 3heteroatoms selected from O, N, and S, (C₅-C₈) cycloalkyl, or 3- to7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected fromO, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one to three R₁₃; R₈ is—(C₀-C₄)-alkylene-(C₆-C₁₄) aryl optionally substituted with one to threeR₉; each R₉ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₈) cycloalkyl, 3- to7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected fromO, N, and S, —(C₀-C₃)-alkylene-(C₆-C₁₄) aryl, —(C₀-C₃)-alkylene-5- or6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N,and S, —NH₂, —OH, —C(O)R₂₃, —C(O)NR₂₃R₂₄, —NR₂₃C(O)R₂₄, —NR₂₃R₂₄,—S(O)_(q)R₂₃, —S(O)_(q)NR₂₃R₂₄, —NR₂₃S(O)_(q)R₂₄, oxo, —P(O)((C₁-C₆)alkyl)₂, —P(O)((C₆-C₁₄) aryl)₂, —SiMe₃, —SF₅, —O—(C₆-C₁₄) aryl, CN, or—O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selectedfrom O, N, and S, wherein alkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one to three R₁₉; eachR₁₃ is independently D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,(C₆-C₁₄) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from O, N, and S, (C₃-C₈) cycloalkyl, 3- to 7-memberedheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, andS, —O—(C₆-C₁₄) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3heteroatoms selected from O, N, and S, —O-3- to 7-memberedheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, andS, —O—(C₃-C₈) cycloalkyl, —C(O)O(C₁-C₆) alkyl, —C(O)NR₂₆R₂₇,—S(O)_(q)NR₂₆R₂₇, NR₂₆R₂₇, —NR₂₆C(O)NR₂₆R₂₇, —NR₂₆C(O)OR₂₇,—NR₂₆S(O)_(q)R₂₇, —NR₂₆C(O)R₂₇, halogen, —P(O)((C₁-C₆) alkyl)₂,—P(O)((C₆-C₁₄) aryl)₂, —SiMe₃, or —SF₅, wherein in the alkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substitutedwith one to three R₁₅; each R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —C(O)(C₁-C₆)alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, —OH, or CN; each R₁₉ is independently at each occurrence(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, —NR₂₆C(O)R₂₇, —NR₂₆S(O)_(q)R₂₇, C(O)R₂₆, —C(O)NR₂₆R₂₇,—NR₂₆R₂₇, —S(O)_(q)R₂₆, —S(O)_(q)NR₂₆R₂₇, —P(O)((C₁-C₆) alkyl)₂,—P(O)((C₆-C₁₄) aryl)₂, —SiMe₃, —SF₅, —OH, or CN; each R₂₀ isindependently at each occurrence (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —NH₂, or CN; each R₂₃ andR₂₄ is independently H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl,(C₆-C₁₄) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatomsselected from O, N, and S, (C₅-C₈) cycloalkyl, or 3- to 7-memberedheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, andS, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl are optionally substituted with one to three R₂₅; eachR₂₆ and R₂₇ is independently at each occurrence H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₆-C₁₄) aryl, 5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S,(C₅-C₈) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to3 heteroatoms selected from O, N, and S, wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl areoptionally substituted with one to three substituents independentlyselected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)haloalkoxy, —NH₂, (C₁-C₆) alkylamino, or di(C₁-C₆) alkylamino; m is 0,1, 2, 3, or 4; n is 0, 1, 2 or 3; q is independently at each occurrence0, 1, or 2; provided that the compound is further characterized by anyone or more of the following: i. R₆ is (C₆-C₁₄) aryl, 5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S,(C₅-C₈) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to3 heteroatoms selected from O, N, and S, wherein aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one tothree R₁₃; or ii. each R₁₃ is independently (C₆-C₁₄) aryl, 5- or6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N,and S, (C₃-C₈) cycloalkyl, 3- to 7-membered heterocycloalkyl comprising1 to 3 heteroatoms selected from O, N, and S, —O-5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S,—O-3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatomsselected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are substituted with one to three R₁₅.
 2. The compoundof claim 1, wherein n is
 1. 3. The compound of claim 1, wherein m is 0.4. The compound of claim 3, wherein n is
 1. 5. The compound of claim 4,wherein R₂ is 3-butyl.
 6. The compound of claim 5, wherein R₈ is—(C₀)-alkylene-(C₆) aryl.
 7. The compound of claim 6, wherein R₈ is—(C₀)-alkylene-(C₆) aryl unsubstituted with R₉.
 8. The compound of claim7, wherein R₆ is H.
 9. The compound of claim 7, wherein R₆ is (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen other than Cl,CN, NO₂, or —NH₂.
 10. The compound of claim 7, wherein R₆ is (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogenother than Cl, CN, NO₂, —NH₂, —NHC(O)(C₁-C₆) alkyl, wherein the alkyl isoptionally substituted with one to three R₁₃; each R₁₃ is independently(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, CN, —OH, —NH₂, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl,(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, 3- to 7-memberedheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, andS, wherein in the alkyl or heterocycloalkyl are optionally substitutedwith one to three R₁₅; and each R₁₅ is independently (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,—C(O)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH,or CN.
 11. The compound of claim 7, wherein R₆ is —NHC(O)(C₁-C₆) alkyl.12. The compound of claim 11, wherein the alkyl of R₆ is substitutedwith one R₁₃.
 13. The compound of claim 12, wherein R₁₃ is (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,CN, —OH, —NH₂, 3- to 7-membered heterocycloalkyl comprising 1 to 3heteroatoms selected from O, N, and S, wherein the alkyl orheterocycloalkyl are optionally substituted with one to three R₁₅; andeach R₁₅ is independently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, halogen, —NH₂, (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, —OH, or CN.
 14. The compound of claim 13, whereinR₁₃ is a 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatomsselected from O, N, and S, wherein the heterocycloalkyl is optionallysubstituted with one to three R₁₅.
 15. The compound of claim 14, whereinR₁₃ is a 6-membered heterocycloalkyl comprising 1 to 3 heteroatomsselected from O, N, and S, wherein the heterocycloalkyl is optionallysubstituted with one to three R₁₅.
 16. The compound of claim 15, whereinR₁₃ is a piperazinyl and R₁₅ is (C₁-C₆) alkyl.
 17. A compound of Formula(Id):

or a pharmaceutically acceptable salt thereof, wherein: R₂ is (C₁-C₆)alkyl substituted with R₈; R₆ is —NHC(O)(C₁-C₆) alkyl, wherein the alkylis substituted with R₁₃; R₈ is —(C₀-C₄)-alkylene-(C₆) aryl; each R₁₃ isindependently (C₆-C₁₄) aryl, 5- or 6-membered heteroaryl comprising 1 to3 heteroatoms selected from O, N, and S, (C₃-C₈) cycloalkyl, 3- to7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected fromO, N, and S, —O—(C₆) aryl, —O-5- or 6-membered heteroaryl comprising 1to 3 heteroatoms selected from O, N, and S, —O-5- to 6-memberedheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, andS, —O—(C₅-C₆) cycloalkyl, wherein in the aryl, heteroaryl, cycloalkyl,and heterocycloalkyl are substituted with one to three R₁₅; each R₁₅ isindependently (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)haloalkoxy, halogen, —C(O)(C₁-C₆) alkyl, —S(O)_(q)(C₁-C₆) alkyl, —NH₂,(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH, or CN; m is 0; and nis
 1. 18. The compound of claim 17, wherein R₂ is (C₃) alkyl; R₁₃ is apiperazinyl; R₆ is —NHC(O)(C₂) alkyl, wherein the alkyl is substitutedwith one R₁₅; and R₁₅ is methyl.
 19. A compound of Formula (Id):

or a pharmaceutically acceptable salt thereof, wherein: R₂ is (C₁-C₆)alkyl substituted with one R₈; R₆ is —NHC(O)(C₁-C₆) alkyl substitutedwith one R₁₃; R₈ is —(C₀)-alkylene-(C₆) aryl; R₁₃ is 5- or 6-memberedheteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S,substituted with one to three R₁₅; each R₁₅ is independently (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,—C(O)(C₁-C₆) alkyl, —NH₂, (C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, —OH,or CN; m is 0; and n is
 1. 20. The compound of claim 19, wherein R₁₃ isa piperazinyl substituted with one R₁₅; R₁₅ is methyl; and R₂ is (C₃)alkyl.